This Program Project if comprised of four highly integrated scientific projects that address a central theme, that are directed by a multidisciplinary, collaborative team of investigators and that are supported by the services of three essential core facilities (administration, molecular histology and transgenic animals). The central theme of our Program Project is that local and systemic factors such as interleukin-1 (IL-1), tumor necrosis factor (TNF) and glucocorticoids will alter osteoblast and osteoclast differentiation and that an understanding of these activities and their regulation will help us elucidate the pathogenesis of osteoporosis. The scientific projects will test the following hypotheses: that estrogen withdrawal due to ovariectomy increases IL-1 and TNF activity and/or production (Projects 1 and 2); that these effects will increase osteoclast differentiation and decease osteoblast differentiation, thus disturbing the coupling of resorption and formation and causing a net loss of bone mass (Projects 1 and 2); that inhibition of IL-1 and TNF responses in bone either by gene knock-out of specific receptors for these cytokines or by targeted overexpression of IL-1 and TNF antagonists to bone will blunt bone loss due to estrogen withdrawal (Projects 1 and 2;) that in vivo glucocorticoids will deplete the bone marrow of osteoprogenitors, an effect that will contribute to its inhibition of bone formation (Project 3); that targeted overexpression of insulin-like growth factor to bone will blunt the inhibitory effects of glucocorticoids on bone formation (Project 3): and that bone marrow stromal cells have the potential of being used as vehicles for somatic gene therapy of bone (Project 4). Projects 1,2 and 3 will test the effects of targeted transgenic expression of molecules that block or reverse the activity of pathogenic factors while Project 4 will determine whether new methods of somatic gene therapy will provide a feasible approach for targeting these molecules to bone. We believe the results of our experiments will have therapeutic implications for the treatment of osteoporosis.